Microbiome-Apo ε-Gender-Neurometabolic Axis in Older Adults of MiaGB Consortium Cohort

Cognitive impairment with age remains a debilitating health problem in older adults, which increases the risk of developing dementia, including Alzheimer’s disease (AD) and related dementia (ADRD). These ailments cause dramatic burdens in patients, families, and healthcare systems, and we still do not fully understand the etiology of ADRD, thereby hindering diagnosis, prevention, and treatment of these debilitating problems. Multiple emerging evidence show that gut microbiome plays crucial role in pathology of ADRD, but the role of microbiome components like bacteriome and virome, genotype, gender, and metabolic health interactions remains poorly understood. Herein, we explored the interactions of microbiome with Apoε genotypes, gender, and the BMI of older adults from the MiaGB consortium. We analyzed the gut bacteria and virome of older adults with and without the Apoε4 genotype. We identified unique microbial signatures associated with Apoε4 presence, cognitive impairment (CI), gender, and BMI. Apoε4 carriers exhibited lower cognitive functions, depletion of bacteria like Verrucomicrobia, Rikenella, Akkermansia, and Akkermansia muciniphila [also in (Apoε4+ female) and (Apoε4+ overweight)], and Faecalibacterium praunistzii, while Eggerthella sinensis, Anaerotruncus colihominis, and lytic viruses like Streptococcus virus DT1 and Streptococcus virus PhiABc2 were significantly enriched versus Apoε4- subjects. In Apoε4+ females, higher abundances of Clostridium, Gordonibacter, and virome ( Lactococcus phage J1, Escherichia phage TL2011b ) were also observed, while male carriers had higher Lactobacillus phage biL310 and Clostridium phage vB CpeS CP51. However, Apoε4+ males have lower Oscillospiraceae, Tannerellaceae, Fusicatenibacter, and Bacteroides thetaiotaomicron relative to the Apoε4- male cohort. Also, overweight Apoε4+ had lower Candidatus melainabacteria, Anaeromassilibacillus, Lactonifractor, and Lactobacillus but enriched virome like Lactococcus phage J1, Lactococcus virus c2, and Bacteroides phage B124_14. Impairments in microbial pathways involved in L-tryptophan synthesis, catecholamine degradation, preQ0 synthesis, and glycogen degradation were also noted in Apoε4+ subjects. Our findings emphasize the link of gut bacteriome and virome signature differences according to Apoε4, gender, and neurometabolic risk and highlight the need for further research to understand the mechanisms and personalized strategies to diagnose and prevent/treat ADRD in older adults. Ed and Ethel Moore Alzheimer’s Disease Research Program, Florida Dept. of Health (22A17), and NIH, NIA (R56AG069676, R56AG064075, RF1AG071762, R21AG072379, U01AG076928) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.